Glucocorticoids (glucocorticosteroids) are a class of steroid hormones characterized by an ability to bind with the cortisol receptor found in the cells of almost all vertebrate tissues and trigger similar effects. Glucocorticoids are distinguished from other steroids such as sex steroids by the specific receptors, target cells, and effects. Cortisol (or hydrocortisone) is the most important natural human glucocorticoid.
Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. This is particularly evident when they are administered at pharmacologic doses, but also is important in physiologic immune responses. As a consequence, glucocorticoids are widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis, and as adjunctive therapy for conditions such as autoimmune diseases. On the other hand, excessive glucocorticoid levels, resulting from administration as a drug or hyperadrenocorticism have side-effects on many systems, some examples including inhibition of bone formation, suppression of calcium absorption and delayed wound healing.
A variety of synthetic glucocorticoids, some far more potent than cortisol, have been developed for therapeutic use. They differ in the pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water). Because they are absorbed well through the intestines, they are primarily administered per os (by mouth), but also by other ways like topically on skin.
Methylprednisolone (pregna-1,4-diene-3,20-dione,11,17,21-trihydroxy-6-methyl-,(6α,11β). C22H30O5, MW 374.48) is one example of a therapeutically potent synthetic glucocorticoid drug, which, due to its hydrophobic character, is usually taken orally. Like most adrenocortical steroids, methylprednisolone is typically used for its anti-inflammatory properties. However, glucocorticoids have a wide range of effects, including changes in metabolism and immune responses. Similar to other corticosteroids, the list of diseases or pathological conditions for which methlyprednisolone is effective is rather large. Common uses includes arthritis therapy, and short-term treatment of bronchial inflammation due to various respiratory diseases. while hightly effective, their systemic application is limited because of a high incidence of serious adverse effects, especially related to long-term treatment.
Efficacy and safety studies of systemic administration of glucocorticoids, revealed that in addition to the profound activity of the drug in many different tissues, these drugs have rapid clearance from plasma thereby requiring high and frequent dosing to obtain effective amounts at the target site.
Thus, alternative approaches for parenteral administration were investigated. For example, developing loco-regional administration of glucocorticoids (e.g. by the use of inhalers in asthma and in intraarticular injection in arthritis) enabled the use of lower doses of the steroid while achieving sufficient drug levels in a lesion, with minimal side effects.
A further approach included targeting of the drug to the target tissue by the use of a suitable carrier, such as liposomes.
First attempts to encapsulate corticosteroids in liposomes were performed by Fildes F J et al. [J Pharm. Pharmacol. 30(6):337-42 (1978)] which included steroid encapsulation in the liposome's lipid bilayer. This approach was based on the understanding that corticosteroids are hydrophobic in nature. However, such liposomal formulations turned to be unsuitable for clinical applications.
Efforts were also made in developing “soluble” glucocorticoids. Examples include succinate derivatized steroids such as hydrocortisone hemisuccinate sodium salt and Methylprednisolone hemisuccinate sodium salt. Another group of soluble glucocorticoids include the phosphate derivatives of steroids. While rendering the steroid water-soluble enabled the use of the acidic steroids for injection, it was shown that these “pro-drugs” are completely cleared from plasma in less than 6 hours post injection. [Mishina E V et al Pharm Res 13(l):141-5 (1996)]
The combination of acidic steroids with liposomes was also investigated. Schmidt et al. [Schmidt J et al. Brain 126(8):1895-1904 (2003)] describe a formulation of polyethyleneglycol (PEG)-coated long-circulating sterically stabilized liposomes encapsulating prednisolone phosphate (one of the water soluble pro-drug steroids) and its beneficial effect in treating multiple sclerosis as compared to the free form of the steroid. However, attempts to similarly encapsulate methylprednisolone hemisuccinate (a weak acid) failed, as it led to an unstable formulation.
Further, encapsulation in liposomes of triamcinolone acetonide phosphate, a water soluble strong acid derivative of triamcinolone (pKa below 2) was described [Gonzalez-Rothi, Ricardo J et al. Pharmaceutical Research 13(11):1699-1703 (1996)]. The liposomal formulation was prepared by passive loading of the acidic corticosteroid into the liposomes and used as an injectable dosage form (intravenous or intratracheal) for treating pulmonary conditions. Further, in ex vivo stability studies it was shown that after 24 hours the liposome retained more than 75% of the acidic corticosteroid.